WO2007142288A1 - Traitement d'une maladie ischémique à l'aide d'érythropoïétine - Google Patents

Traitement d'une maladie ischémique à l'aide d'érythropoïétine Download PDF

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Publication number
WO2007142288A1
WO2007142288A1 PCT/JP2007/061525 JP2007061525W WO2007142288A1 WO 2007142288 A1 WO2007142288 A1 WO 2007142288A1 JP 2007061525 W JP2007061525 W JP 2007061525W WO 2007142288 A1 WO2007142288 A1 WO 2007142288A1
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WIPO (PCT)
Prior art keywords
peripheral blood
subject
erythropoietin
mononuclear cells
cells
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PCT/JP2007/061525
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English (en)
Japanese (ja)
Inventor
Toshio Matsumoto
Tetsuya Kitagawa
Masahiro Abe
Masashi Akaike
Kazunari Nagayoshi
Kaname Yamamoto
Masato Higuchi
Original Assignee
The University Of Tokushima
Chugai Seiyaku Kabushiki Kaisha
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Priority to JP2008520614A priority Critical patent/JP5326079B2/ja
Application filed by The University Of Tokushima, Chugai Seiyaku Kabushiki Kaisha filed Critical The University Of Tokushima
Priority to AU2007255717A priority patent/AU2007255717B2/en
Priority to CN2007800209636A priority patent/CN101460188B/zh
Priority to EP07744855A priority patent/EP2047859A4/fr
Priority to MX2008015392A priority patent/MX2008015392A/es
Priority to BRPI0712063-0A priority patent/BRPI0712063A2/pt
Priority to NZ573792A priority patent/NZ573792A/en
Priority to CA002654154A priority patent/CA2654154A1/fr
Priority to US12/303,669 priority patent/US20090280094A1/en
Publication of WO2007142288A1 publication Critical patent/WO2007142288A1/fr
Priority to IL195648A priority patent/IL195648A0/en
Priority to NO20085098A priority patent/NO20085098L/no
Priority to HK09107647.3A priority patent/HK1128419A1/xx

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4621—Cellular immunotherapy characterized by the effect or the function of the cells immunosuppressive or immunotolerising
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/46433—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/10—Growth factors
    • C12N2501/14—Erythropoietin [EPO]

Definitions

  • the present invention relates to a method for regenerating blood vessels, a method for treating ischemic diseases, and a composition used in these methods.
  • Peripheral circulatory disturbance is caused by stenosis of blood vessel lumen, generation of thrombus, occlusion of blood vessel, vasculitis, contraction of blood vessel, increase of blood viscosity, etc. It is a medical condition that falls into a state.
  • transplantation of bone marrow-derived mononuclear cells to an ischemic site enhances angiogenesis, and bone marrow-derived mononuclear cell transplantation is considered to be one of the treatment methods for peripheral circulation disorders.
  • it was necessary to collect bone marrow from the patient which was a burden on the patient.
  • EP0 Erythropoietin
  • EP0 is an acidic glycoprotein hormone that promotes the differentiation and proliferation of erythroid progenitor cells, and is produced mainly from the kidney.
  • the most abundant red blood cells in the blood are destroyed in the spleen after functioning for a certain period of time (average life span is about 120 days in humans).
  • the red blood cell count is always kept constant.
  • EPO plays a central role in maintaining the homeostasis of such living red blood cells.
  • Clinically, EP 0 is used for anemia treatment and pre- and post-operative management.
  • EPO has been reported to have angiogenesis-promoting action and be useful as a therapeutic agent for ischemic diseases (Besarab A et al., The New England Journal of Medicine, 3 39 (9 ), 584-590, (1998), Heeschen C et al., Blood, 102 (4), 1340-1346, (2003), Bahlmann FH et al "Blood, 103 (3), 921-926, (2004) , Smith KJ et al., Cardiovascular Research, (59), 538-548, (2003), Bahlmann FH et al., Kidney International, 64, 1648-1652, (2003)).
  • EPO has been reported to promote the recruitment of vascular endothelial progenitor cells into peripheral blood (Heeschen C et al., Blood, 102 (4), 1340-1346, (2003), Bahlmann FH et al ., Blood, 103 (3), 921–926, (2004))
  • Non-patent literature l Besarab A et al., The New England Journal of Medicine, 339 (9), 584-590, (1998)
  • Non-Patent Document 2 Heeschen C et al., Blood, 102 (4), 1340-1346, (2003)
  • Non-Patent Document 3 Bahlmann F H et al., Blood, 103 (3), 921-926, (2004)
  • Non-Patent Document 4 Smith K J et al., Cardiovascular Research, (59), 538-548, (2003)
  • Non-Patent Document 5 Bahlmann F H et al., Kidney International, 64, 1648-1652, (200
  • the present inventors have promoted the mobilization of mononuclear cells in peripheral blood by administering EPO, and the mononuclear cells thus mobilized by EPO have an ischemic disease. It was found to be particularly useful for treatment.
  • the present invention provides a composition for mobilizing mononuclear cells in peripheral blood for use in the treatment of ischemic diseases or for revascularization, comprising erythropoietin as an active ingredient.
  • the recruited mononuclear cells are administered to the subject after being collected from the subject.
  • composition is also preferably administered to the subject 3 to 12 days before peripheral blood collection.
  • the present invention also provides peripheral blood collected from a subject previously administered with erythropoietin.
  • a composition for treating ischemic disease and a composition for vascular regeneration, each of which comprises isolated mononuclear cells as an active ingredient.
  • erythropoietin is preferably administered 3 to 12 days before collection of peripheral blood.
  • the present invention also provides a composition for mobilizing CD34-positive cells in peripheral blood for use in the treatment of ischemic disease or revascularization, comprising erythropoietin as an active ingredient.
  • the present invention relates to a method for producing mononuclear cells for revascularization, characterized in that mononuclear cells are separated from peripheral blood collected from a subject previously administered with erythropoietin, and A method for producing mononuclear cells for treatment of ischemic disease is provided.
  • the present invention provides the following steps:
  • a method for treating an ischemic disease and a method for regenerating blood vessels comprising the step of administering the collected peripheral blood mononuclear cells to a desired site of the subject.
  • FIG. 1 shows the results of FACS analysis in which the mobilization of hematopoietic stem cells by erythropoietin was measured.
  • FIG. 2 shows the results of measuring the number of colonies of hematopoietic stem cells mobilized by erythropoietin administration.
  • FIG. 3 shows an angiographic photograph one month after transplantation of peripheral blood mononuclear cells of a patient (case 3) administered erythropoietin.
  • the present invention relates to a composition for mobilizing mononuclear cells in peripheral blood for use in the treatment of ischemic diseases or for revascularization, comprising erythropoietin as an active ingredient. .
  • a composition for mobilizing mononuclear cells promotes the differentiation and proliferation of pluripotent stem cells present in various organs and releases mononuclear cells containing pluripotent stem cells into the blood.
  • the mononuclear cells thus mobilized can be collected from the subject's peripheral blood and administered to the subject for treatment of ischemic disease and revascularization.
  • the subject is preferably a patient suffering from an ischemic disease or a patient requiring revascularization treatment.
  • the number of times erythropoietin is administered to a subject before collecting peripheral blood mononuclear cells is not particularly limited, and may be any number, but is usually:! To 3 times.
  • the first erythropoietin is administered systemically (eg, subcutaneous injection or intravenous injection) to the subject about 2 weeks before collecting peripheral blood mononuclear cells, and blood is stored (congested blood) about 1 week after that. ),
  • the second erythropoietin is administered systemically.
  • the desired peripheral mononuclear cells can be collected from the peripheral blood.
  • peripheral blood mononuclear cells when administered twice, for example, about 1 week before collecting peripheral blood mononuclear cells, the subject was given the first erythropoietin systemically, and about 1 week later after the second erythropoietin was locally administered.
  • Target peripheral mononuclear cells can be collected from peripheral blood.
  • the subject can be systemically administered with Ellis mouth poitin, and the desired peripheral blood mononuclear cells can be collected about one week after the administration.
  • the erythropoietin administered at a time is usually administered at a dose of 1000 U / body to 100,000 U / body, preferably 3000 U / body to 12000 U / body (eg, 6000 U / body).
  • the dose for an individual subject is determined by a physician taking into account the subject's age, weight, symptoms, route of administration, and the like. Therefore, the dose for administering erythropoietin in the present invention is not limited to these doses.
  • Erythropoietin is usually administered parenterally, for example, by injection (subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, etc.), transdermal, transmucosal, nasal, transpulmonary, etc. Oral administration is also possible.
  • Peripheral blood mononuclear cells are mononuclear cells present in peripheral blood.
  • Mononuclear cells also called monocyte cells, are cells in one stage of differentiation of macrophage cells that are mainly present in blood.
  • hematopoietic stem cells differentiate into monoblasts and premonocytes, and then differentiate into mononuclear cells and are released into the blood.
  • mononuclear cells migrate to tissues, macrophages and dendritic cells Differentiate into vesicles and histocytes.
  • the present invention relates to a method for obtaining mononuclear cells or a method for producing mononuclear cells for transplantation, comprising the following steps:
  • about 1 week is usually 3 to 12 days, preferably 5 to 9 days (for example, 6
  • the present invention relates to a composition for mobilizing CD34-positive cells in peripheral blood for use in the treatment of ischemic disease or revascularization, comprising erythropoietin as an active ingredient.
  • CD34 is a blood stem cell antigen and is expressed not only in blood stem cells but also in vascular endothelial cells, vascular endothelial precursor cells, stromal cells and the like. Since CD34 positive cells such as vascular endothelial progenitor cells are known to be involved in angiogenesis, CD34 positive cells in mononuclear cells to be transplanted can be used to treat ischemic diseases or to obtain revascularization effects. It is desirable to increase the ratio.
  • the population of mononuclear cells mobilized in peripheral blood by the method of the present invention usually contains a sufficient amount of CD34 positive cells to obtain an ischemic disease therapeutic effect or a blood vessel regeneration effect. Furthermore, isolating or concentrating CD34-positive cells from mononuclear cells obtained by the method of the present invention to increase the proportion of CD34-positive cells is a transplant for the treatment of ischemic diseases or blood vessel regeneration. This is particularly useful when
  • the ratio of CD34 positive cells in mononuclear cells is high means that the ratio of CD34 positive cells in mononuclear cells is 1% or more, preferably 2% or more, and more preferably. 3% or more.
  • the upper limit of the proportion of CD34 positive cells in mononuclear cells is For example, 99. 99%, 99.9%, 99%, etc.
  • the force is 100% in theory.
  • the CD34-positive cells contained in the mononuclear cells obtained according to the present invention may be further CD45-positive.
  • CD45 is a leukocyte common antigen and the major membrane glycoprotein of hematopoietic cells.
  • peripheral blood mononuclear cells from the subject can be performed according to a conventional method. For example, after collecting blood-derived mononuclear cells directly from blood apheresis and collecting peripheral blood leukocytes by removing a substantial portion of red blood cells, granulocytes and platelets by centrifuging if necessary. The resulting peripheral blood leukocytes can be washed by centrifugation or the like to obtain mononuclear cells.
  • Peripheral blood mononuclear cells obtained in this manner may be further processed by addition, isolation, purification, or the like.
  • desired cells such as CD34 positive cells and vascular endothelial progenitor cells may be further concentrated or isolated from the collected peripheral blood mononuclear cells.
  • CD34 positive cells for example, peripheral blood mononuclear cells are reacted with anti-CD34 antibody and then reacted with magnetic beads to which anti-mouse IgG antibody is bound. After adhering, collect CD34 positive cells bound to magnetic beads with a plate magnet, and separate the magnetic beads by enzymatic treatment to recover only CD34 positive cells or with CD34 antibody bound to a fluorescent dye. Substantially pure cells can be obtained by reacting and collecting with a fluorescent cell sorter.
  • Peripheral blood mononuclear cells prepared according to the present invention can be administered to a subject for the purpose of treating ischemic disease. That is, in another aspect, the present invention relates to a method for treating an ischemic disease including the following steps.
  • Ischemic disease is caused by a decrease in blood flow in the blood vessel due to various factors such as narrowing of the lumen of the blood vessel, formation of a thrombus, occlusion of the blood vessel, vasculitis, vasoconstriction, and increased blood viscosity.
  • ischemic diseases include peripheral circulation disorders, ischemic heart disease (Ischemic cardiomyopathy, myocardial infarction, ischemic heart failure, etc.), ischemic cerebrovascular disorder, ischemic kidney disease, ischemic lung disease, ischemic disease related to infection, and the like.
  • Peripheral circulatory disturbance is caused by vascular stenosis, thrombus formation, vascular occlusion, vasculitis, vasoconstriction, increased blood viscosity, etc., resulting in decreased blood flow in peripheral arteries and ischemia in peripheral tissues. It is a medical condition that falls into a state.
  • Diseases with peripheral circulatory disturbance include obstructive arteriosclerosis, chronic arterial occlusion such as Buerger's disease, progressive systemic sclerosis, systemic lupus erythematosus, Reino's disease, vibration disease, aneurysm, vasculitis And so on.
  • the disease that is a suitable target of the therapeutic agent of the present invention is peripheral circulatory disorder, and is particularly preferably obstructive arteriosclerosis or purger disease.
  • peripheral blood mononuclear cells prepared according to the present invention can be administered to a subject for the purpose of revascularization. That is, in another aspect, the present invention relates to a method for regenerating a blood vessel comprising the following steps:
  • Regenerating blood vessels in the present invention means promoting angiogenesis and / or promoting the growth and development of blood vessels.
  • the blood vessels that are promoted by the method of the present invention are not particularly limited, but arteries are preferred, and peripheral arteries are particularly preferred.
  • the regeneration of blood vessels can be measured by methods known to those skilled in the art. For example, capillary density can be measured using Alforce phosphatase staining or the like.
  • the desired site usually refers to a site where ischemia has occurred and a site where blood vessel regeneration is desired.
  • the desired site is such other site. May be.
  • Specific examples of the local administration site include lower limb skeletal muscle, upper limb skeletal muscle, and heart (myocardium).
  • the number of cells when the collected mononuclear cells are administered or transplanted to a desired site is not particularly limited, but is usually 1.0 X 10 7 to 1.0 X 10 12 , preferably ⁇ ⁇ to ⁇ ⁇ There are ⁇ pieces.
  • Local administration is a method in which cells can be efficiently administered locally to an affected area without greatly affecting the whole body. Local administration can be performed using a normal syringe, needle, local needle or the like.
  • the mononuclear cells When the collected mononuclear cells are administered to a desired site, the mononuclear cells may be administered alone or together with other substances.
  • the substance administered together when administering mononuclear cells is not particularly limited, but is preferably a substance that enhances the vascular regeneration action.
  • the EP 0 used in the present invention is a force that can be used with any EP 0, preferably a highly purified EP 0, and preferably has substantially the same biology as mammalian EPO, particularly human EP 0. Have a positive activity.
  • the EPO used in the present invention may be produced by any method, for example, natural human EPO (Japanese Patent Publication No. 1-38800, etc.) obtained by purification from human-derived extracts, It can also be produced by various methods using E. coli, yeast, Chinese hamster ovary cells (CHO cells), C127 cells, COS cells, myeloma cells, BHK cells, insect cells, etc. by genetic engineering techniques. Separated and purified human EPO can be used.
  • the EPO used in the present invention is preferably an EPO produced by a genetic engineering technique, and an EPO produced using mammalian cells (especially CHO cells) is preferred (for example, Japanese Patent Publication No. 1-44317). Kenneth Jacobs et al., Nature, 313 806-810 (1985), etc.).
  • the EPO obtained by the genetic recombination method has the same amino acid sequence as that of naturally-occurring EPO, or one in which one or more amino acids in the amino acid sequence are deleted, substituted, or attached with calories. It may be one having the same biological activity as naturally occurring EPO.
  • Amino acid deletion, substitution, addition and the like can be performed by methods known to those skilled in the art. For example, those skilled in the art will recognize site-directed mutagenesis (Gotoh, T. et al. (1995) Gene 152,271-275; Zoller, MJand Smith, M. (1983) Methods Enzymol. 100, 468-500; Kr amer, W. et al. (1984) Nucleic Acids Res.
  • amino acid side chain properties include hydrophobic amino acids (A, I, L, M, F, P, W, Y, V), hydrophilic amino acids (R, D, N, C, E, Q, G, H, K, S, T), amino acids with aliphatic side chains (G, A, V, L, I, P), amino acids with hydroxyl-containing side chains (S, T, ⁇ ), sulfur atoms
  • Amino acids with side chains C, M
  • amino acids with carboxylic acid or amide-containing side chains D, N, E, Q
  • amino groups with base-containing side chains R, K, ⁇
  • aromatics Amino acids having side chains H, F, Y, W
  • H, F, Y, W can be mentioned (the parentheses indicate one-letter characters of amino acids).
  • a fusion protein of EPO and another protein it is also possible to use a fusion protein of EPO and another protein.
  • DNA encoding EPO and DNA encoding another protein are linked so that the frames coincide with each other, introduced into an expression vector, and expressed in a host. That's fine.
  • Other proteins to be subjected to fusion with the EPO of the present invention are not particularly limited.
  • EPO electroactive polymer
  • Examples of chemically modified EP 0 include, for example, EP 0 combined with a compound such as polyethylene glycol 'vitamin B12 or the like or an inorganic or organic compound.
  • the EPO used in the present invention may be an EPO derivative.
  • an EPO derivative means EPO modified with an amino acid in an EP molecule or EP modified with a sugar chain in an EPO molecule.
  • Sugar chain modifications in the EPO molecule include addition, substitution, and deletion of sugar chains.
  • preferred sugar chain modifications in the present invention May include deletion of sialic acid in the EPO molecule.
  • both EPO produced by recombinant animal cells and urine-derived EPO are obtained as EPO compositions containing various EPOs having different sugar chain structures.
  • the number of sialic acids added to the EP molecule in the EPO composition varies depending on the individual EPO molecule S, and usually 11 to 15 sialic acids are added to one EP molecule. By removing these sialic acids, it is possible to produce a cashoid-treated EPO (Cashiaro EPO).
  • the number of sialic acids to be removed during the cationization is not particularly limited, and all sialic acids may be removed, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 11, 12, 13, or 14 sialic acids may be removed.
  • the preferred mouth opening EPO has 10 or less sialic acid added to the EPO molecule, more preferably 5 or less, and particularly preferably 2 or less.
  • the number of sialic acids is the average number of sialic acids on the EPO molecules contained in the EPO composition. The average sialic acid per molecule can be measured by methods known to those skilled in the art (EP0428267, etc.).
  • EPO from which sialic acid has been removed can be prepared by methods known to those skilled in the art. For example, it can be prepared by treating EPO with an enzyme such as sialidase. is there.
  • an enzyme such as sialidase. is there.
  • a commercially available sialidase can be used (Japanese Patent No. 005-507426, Nobuo Imai et al., Eur. J. Biochem, 194, 457-462 (1990), etc.).
  • amino acid modification in the EPO molecule examples include force rubamylation, pyotination, amidineation, acetylation, guanidination, and the like.
  • Preferred amino acid modification in the present invention is carnocumyl. Is.
  • amino acid residue to be modified is not particularly limited.
  • lysine arginine, glutamic acid, tributophane and the like.
  • Preferred amino acid modified in the present invention is lysine.
  • EP0 in which a lysine is carbamylated can be mentioned (Marcel L et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science, 2004; 305: 239, riordaliso E et al. A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury. PNAS, 2005; 102: 20 46, etc.).
  • EPO is a suspending agent, solubilizer, stabilizer, tonicity agent, preservative, adsorption inhibitor, surfactant, diluent, excipient, pH, according to techniques known in the art.
  • Conditioning agents, soothing agents, buffering agents, sulfur-containing reducing agents, antioxidants and the like can be added as appropriate to prepare a preparation.
  • suspending agent examples include methyl cellulose, polysonoleate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like.
  • solution adjuvant examples include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, tuna gol, castor oil fatty acid ethyl ester, and the like.
  • Examples of the stabilizer include dextran 40, methylcellulose, gelatin, sodium sulfite, and sodium metasulfite.
  • amino acid added as stabilizers include free amino acids, salts such as sodium salts, potassium salts and hydrochlorides thereof.
  • One or more amino acids can be added in combination.
  • the amino acid added as a stabilizer is not particularly limited, but preferred amino acids include leucine, tryptophan, serine, glutamic acid, arginine, histidine, and lysine.
  • Examples of the isotonic agent include D-mannitol, sorbate and the like.
  • Examples of the preservative include methyl noroxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, black mouth talesol and the like.
  • Examples of the adsorption inhibitor include human serum anolebumin, lecithin, dextran, ethylene oxide / propylene oxide copolymer, hydroxypropylcellulose, methylcellulose, polyoxyethylene hydrogenated castor oil, polyethylene glycol and the like. it can.
  • Surfactants include nonionic surfactants such as sorbitan fatty acid esters such as sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate; glycerin monocaprylate, glycerin monomylate, glycerin monostearate, etc.
  • Glycerin fatty acid esters of polyglycerin fatty acid esters such as decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate; polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene
  • Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitate polystearate, polyoxyethylene sorbite fatty acid esters such as polyoxyethylene sorbite tetraoleate; polyoxyethylene glycerin fatty acid esters such as polyoxyethylene glyceryl monostearate; Polyethylene glycol fatty acid esters such as polyethylene glycol distearate; Polyoxyethylene alkyl etherol such as polyoxyethylene lauryl ether; Polyoxyethylene polyoxypropylene glycol, Polyoxyethylene polyoxypropylene propyl ether, Polyoxyethylene polyoxypropylene Polyoxyethylene polyoxypropylene alkyl ethers such as cetyl ether; polyoxy Polyoxyethylene alkyl phenyl ether such as echelenonyl phenyl ether; Polyoxyethylene hydrogenated castor oil such as polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil (polyoxyethylene hydrogen castor oil); Polyoxyethylene Polyoxyethylene beeswa
  • anionic surfactants For example, an alkyl sulfate having an alkyl group having 10 to 18 carbon atoms, such as sodium cetyl sulfate, sodium lauryl sulfate, sodium oleyl sulfate, etc .; an ethylene oxide such as polyoxyethylene sodium lauryl sulfate; Polyoxyethylene alkyl ether sulfate having an average addition mole number of 2 to 4 and an alkyl group having 10 to 18 carbon atoms; an alkyl group having 8 to 18 carbon atoms such as sodium lauryl sulfosuccinate
  • a Typical examples include ruylsulfosuccinic acid ester salts; natural surface active IJs such as lecithin, dalycerolin lipids; sphingophospholipids such as sphingomyelin; and sucrose fatty acid esters of fatty acids having 12 to 18 carbon atoms.
  • the preparation of the present invention may be supplemented with one or more of these surfactants.
  • Preferred surfactants are polyoxyethylene sorbitan fatty acid esters such as polysorbate 20, 40, 60 or 80, with polysorbates 20 and 80 being particularly preferred.
  • polyoxyethylene polyoxypropylene glycol represented by Poloxamer (Punore Knick F-68 (registered trademark) etc.) is also preferred.
  • sulfur-containing reducing agent examples include N-acetyl cysteine, N-acetyl homo cysteine, thiotate acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, thio Examples thereof include those having a sulfhydryl group such as sodium sulfate, dartathione, and thioalkanoic acids having 1 to 7 carbon atoms.
  • Antioxidants include, for example, erythorbic acid, dibutylhydroxytoluene, butylhydroxyether, ⁇ -tocopherol, tocopherol acetate, L-ascorbic acid and its salts, L-ascorbyl palmitate, L-ascorbic acid stearate, hydrogen sulfite
  • the chelating agent include sodium, sodium sulfite, triamyl gallate, propyl gallate, or disodium ethylenediamine tetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate.
  • inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium hydrogen carbonate, etc .
  • organic salts such as sodium citrate, potassium citrate, sodium acetate, etc.
  • added components may be included.
  • mice C57BL / 6, 9 weeks old were subcutaneously administered once daily with recombinant human EPO (epodine (registered trademark), active ingredient: epoetin beta) at a dose of 100 Aig / kg / day.
  • Control mice were administered subcutaneously in the same manner. On day 5, mice were sacrificed and peripheral blood cells (0.6-lmL) were collected.
  • SIGMA Red blood cell lysing buffer
  • Nonspecific reaction inhibitory antibody (BD-Pharmigen, San Diego, Calif.) CD16 / CD32 (Fc ⁇ c / IIrec-labeled tor) was added at 1 g / 106 cells, and the mixture was incubated on ice for 30 minutes.
  • FITC-conjugated anti-mSca_l antibody (BD pharmingen San Diego, CA)
  • PE_conjugated anti-mCD34 antibody APC_conjugated anti-mc- Kit antibody (BD pharmingen San Diego, CA)
  • APC_Cy7_conjugated anti-mCD3 A cocktail of CD4, CD8a, CD45R / B220, Ly6G (Gr-1), CD1 lb (Mac-1 chain), and Terrl9 antibody was used as a line age marker. After antibody staining, analysis was performed using FACSvantageSE (Becton Dickinson, Mountain View, CA).
  • EPO6000U subcutaneously
  • blood was collected for the purpose of storing blood (approximately 400 ml), and EPO6000U was injected subcutaneously (second time).
  • EPO6000U was injected (third time), and about 10 9 peripheral mononuclear cells were separated from peripheral blood by blood metastasis.
  • Peripheral blood samples were collected before EPO administration, after the second administration, and immediately before affliction, and blood tests (WBC, CRP, CK) and CD34 positive cell count were performed.
  • the isolated peripheral mononuclear cells were injected divided into 50-100 power points into the muscle of the patient's ischemic limb.
  • the effect of angiogenesis therapy was evaluated by observing and measuring the following items before cell transplantation, the day after administration, 1st week, 2nd week, 1 month, 2 months and 6 months
  • Treadmill test Flatland 2. Measure maximum lameness distance or pain appearance distance at 4km / hr Objective evaluation of skin and ulcer lesions: ABPI (Ankle-brachial pressure index), fingertip pleura, treadmill test (walkable) ), Thermography, laser Doppler (LDPI), transcutaneous oxygen partial pressure (TdPO) measurement
  • the proportion of CD34-positive cells in mononuclear cells collected by blood apheresis was 0.02-0.1% (average 0.06%).
  • peripheral blood mononuclear cells collected 1 week after the first EPO administration contain CD34 positive cells that are equal to or more than the mononuclear cells collected 2 weeks later. It was shown that when using mononuclear cells collected one week after administration of EP 0, it is possible to obtain an angiogenesis treatment effect equivalent to or better than the mononuclear cells collected two weeks later.
  • compositions of the present invention are useful for the treatment of ischemic diseases such as peripheral circulatory disturbances.

Abstract

La présente invention concerne un procédé de régénération d'un vaisseau sanguin qui comprend les étapes suivantes : (a) administration d'érythropoïétine à un sujet ; (b) prélèvement d'une cellule mononucléée du sang périphérique chez le sujet ; et (c) administration en un site choisi chez le sujet de la cellule mononucléée du sang périphérique prélevée. Quand de l'érythropoïétine est administrée à un sujet, une cellule mononucléée du sang périphérique (en particulier une cellule CD34-positive) est recrutée dans le sang périphérique du sujet. Le procédé est utilisable pour le traitement d'une maladie ischémique telle qu'une affection vasculaire périphérique.
PCT/JP2007/061525 2006-06-07 2007-06-07 Traitement d'une maladie ischémique à l'aide d'érythropoïétine WO2007142288A1 (fr)

Priority Applications (12)

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BRPI0712063-0A BRPI0712063A2 (pt) 2006-06-07 2007-06-07 tratamento de doenças isquêmicas usando eritropoietina
AU2007255717A AU2007255717B2 (en) 2006-06-07 2007-06-07 Treatment of ischemic disease using erythropoietin
CN2007800209636A CN101460188B (zh) 2006-06-07 2007-06-07 使用促红细胞生成素的局部缺血疾病的治疗
EP07744855A EP2047859A4 (fr) 2006-06-07 2007-06-07 Traitement d'une maladie ischémique à l'aide d'érythropoïétine
MX2008015392A MX2008015392A (es) 2006-06-07 2007-06-07 Tratamiento de enfermedades isquemicas que usan eritropoyetina.
JP2008520614A JP5326079B2 (ja) 2006-06-07 2007-06-07 エリスロポエチンを用いた虚血性疾患の治療
NZ573792A NZ573792A (en) 2006-06-07 2007-06-07 Treatment of ischemic disease using erythropoietin mobilised mononuclear cells
CA002654154A CA2654154A1 (fr) 2006-06-07 2007-06-07 Traitement d'une maladie ischemique a l'aide d'erythropoietine
US12/303,669 US20090280094A1 (en) 2006-06-07 2007-06-07 Treatment of Ischemic Diseases Using Erythropoietin
IL195648A IL195648A0 (en) 2006-06-07 2008-12-02 Pharmaceutical compositions containing erythropoietin for mobilizing mononuclear cells in peripheral blood for treating ischemic diseases
NO20085098A NO20085098L (no) 2006-06-07 2008-12-08 Behandling av ischemisks sykdommer ved bruk av erytropoietin
HK09107647.3A HK1128419A1 (en) 2006-06-07 2009-08-20 Treatment of ischemic disease using erythropoietin

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US (1) US20090280094A1 (fr)
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JP (2) JP5326079B2 (fr)
KR (1) KR20090031547A (fr)
CN (1) CN101460188B (fr)
AR (1) AR061269A1 (fr)
AU (1) AU2007255717B2 (fr)
BR (1) BRPI0712063A2 (fr)
CA (1) CA2654154A1 (fr)
HK (1) HK1128419A1 (fr)
IL (1) IL195648A0 (fr)
MX (1) MX2008015392A (fr)
NO (1) NO20085098L (fr)
NZ (1) NZ573792A (fr)
RU (1) RU2008152746A (fr)
TW (1) TW200815026A (fr)
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JP2020527710A (ja) * 2017-07-18 2020-09-10 ウニベルジテート ロストック ツェントラーレ ウニベルジテーツフェアヴァルトゥング リフェラート １．１ レヒト 心臓血管再生に対する応答の予測方法

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FR2957799B1 (fr) * 2010-03-26 2012-08-17 Inst Des Vaisseaux Et Du Sang Compositions proangiogeniques, leur procede de preparation et leurs utilisations
CN101940590B (zh) * 2010-08-27 2013-09-18 上海士腾生物技术有限公司 促进创伤愈合的制剂及其制备方法
CN101940594B (zh) * 2010-08-27 2013-12-04 上海士腾生物技术有限公司 用于治疗缺血性心血管疾病的制剂及其制备方法
JP5582983B2 (ja) * 2010-11-24 2014-09-03 楠本化成株式会社 水系沈降防止剤
CN105358681B (zh) 2013-06-05 2019-05-21 首尔大学校产学协力团 具有改善的血管生成特性的外周血干细胞及其用途

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US9347044B2 (en) 2009-06-05 2016-05-24 Cellular Dynamics International, Inc. Reprogramming T cells and hematopoietic cells
US10221396B2 (en) 2009-06-05 2019-03-05 FUJIFILM Cellular Dynamics, Inc. Reprogramming T cells and hematopoietic cells
JP2020527710A (ja) * 2017-07-18 2020-09-10 ウニベルジテート ロストック ツェントラーレ ウニベルジテーツフェアヴァルトゥング リフェラート １．１ レヒト 心臓血管再生に対する応答の予測方法
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US20090280094A1 (en) 2009-11-12
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BRPI0712063A2 (pt) 2011-12-20
AR061269A1 (es) 2008-08-13
TW200815026A (en) 2008-04-01
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JP5326079B2 (ja) 2013-10-30
CN101460188B (zh) 2013-09-04
RU2008152746A (ru) 2010-07-20
NO20085098L (no) 2009-02-27
IL195648A0 (en) 2011-08-01
MX2008015392A (es) 2009-05-05
CN101460188A (zh) 2009-06-17
JPWO2007142288A1 (ja) 2009-10-29
EP2047859A1 (fr) 2009-04-15
AU2007255717B2 (en) 2013-07-11
NZ573792A (en) 2011-09-30
HK1128419A1 (en) 2009-10-30
JP2013116919A (ja) 2013-06-13

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